Project Summary/Abstract Type 2 diabetes (T2D) is characterized by both a loss of insulin sensitivity of target tissues (fat, skeletal muscle, liver) and ultimately, impaired insulin secretion from the pancreatic ?-cell1-3. We have identified a novel SWELL1-mediated signaling pathway that regulates both insulin sensitivity and insulin secretion, whereby SWELL1 loss-of-function can both negatively regulate insulin signaling in target tissues4, 5 and insulin secretion from the pancreatic ?-cell6 ? inducing a state of glucose intolerance4, 6 We have also identified a small molecule modulator, Smod1, as a lead compound that acutely inhibits SWELL1-mediated ICl,SWELL (> 90% inhibition) and induces compensatory SWELL1 protein up-regulation (3-fold). Smod1-mediated SWELL1 upregulation is associated with augmented adipocyte insulin signaling (1.5-fold) and enhanced ?-cell insulin secretion (up to 2-fold) in vitro. Smod1 normalizes both glucose tolerance and insulin sensitivity in obese, glucose intolerant mice and in the polygenic KKAy Type 2 diabetes mouse model. We propose that small molecule SWELL1 modulators may represent a ?first-in-class? therapeutic approach to treat obesity- induced insulin resistance and Type 2 diabetes by augmenting both insulin sensitivity and secretion to improve glycemic control in diabetic patients. Importantly, Smod1 has no to very mild effects on non-obese euglycemic mice ? emphasizing a very low risk of hypoglycemic events typically associated with other commonly used anti-diabetic therapies, including sulfonylureas, GLP-1 receptor agonists, and insulin. Finally, very infrequent Smod1 dosing (i.e once a month) may be sufficient to normalize systemic glycaemia in diabetic patients. The objectives of the current proposal are: 1. to establish the proof-of-concept of modulating SWELL1 signaling as a novel therapeutic approach for the treatment of T2D; and 2. To begin to develop a pipeline of SWELL1 modulators to treat T2D. AIM#1: Characterize the therapeutic effect of Smod1 in augmenting insulin sensitivity and secretion in T2D mouse models AIM#2: Explore Smod1 functional chemistry by characterizing Smod1 structural variants for modulation of SWELL1 activity in vitro and in vivo. AIM#3: Perform Absorption, Distribution, Metabolism, Elimination, and Toxicity studies (ADMET) studies on Smod1 and bioactive derivatives The results of Phase 1 will provide proof of concept for the pharmacological modulation of SWELL1 signaling for the treatment of T2D, and will provide an initial class of drug-like small molecules for further development of candidate molecules to ultimately take into humans in the form of a clinical trial for efficacy in T2D patients. We anticipate Phase 2 SBIR funding of drug development efforts as guided by success of the Phase 1 studies here.